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Abstract Introduction Breast cancer is the most frequent type of tumor and the second leading cause of death in women. Metastases are present in nearly 60% of cases at the time of diagnosis with the lymph nodes, skeleton, lungs, brain and liver as the most frequent sites of metastases. Gastrointestinal involvement is rare, present in only 10% of all the cases. There is a very low risk of developing breast cancer in men. Case presentation A 68-year-old man, with a past history of ductal breast cancer, presented with duodenal obstruction. Medical treatment was attempted without success, so he underwent surgery with subtotal gastrectomy and resection of the first portion of the duodenum. Histological examination showed a duodenal metastasis originating from the previous carcinoma of the breast. Five months after surgery, the patient is alive and well. Conclusion Gastrointestinal metastases should be considered in patients with a past history of breast cancer. Surgical treatment should be performed in patients who are symptomatic and in good general condition. To our knowledge this is the only case of a gastrointestinal metastasis from breast carcinoma in a man.

Bisbenzoxazines ( BisBz ) are a relevant model for the diverse bifunctional benzoxazines that are used to increase the polybenzoxazines cross-linking extensions and modulate the final resin properties for various usages. The presence of side products and intermediates during monomer formation can influence the resin characteristics by inducing chain termination and ramifications, affecting the polymerization and cure processes. This work investigated the diverse isomeric intermediates and side products that are present during the BisBz formation from bisphenol A, aniline, and formaldehyde by ion mobility coupled to tandem mass spectrometry (MS/MS) and ion spectroscopy techniques. The species detected in this work suggest that these multifunctional phenols open diverse concurrent reaction pathways based on two main reactive steps: (i) the imine/iminium phenol attack to form a phenylamino intermediate and (ii) the formaldehyde attack followed by dehydration to form the oxazine ring. The species observed also support previous studies of the benzoxazine formation mechanism and showcase the application of advanced analytical techniques in studying complex chemical systems., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

In this study, we present the development of two catalytic processes: a Pd-PEPPSI-catalyzed aminocarbonylation and a Pd(OAc) 2 -Xantphos-catalyzed alkoxycarbonylation of d-glycals, utilizing carbonylative cross-coupling reactions. We explored successfully various types of aromatic amines, as well as alkyl amines and amino acids, to synthesize new d-glycal amides. However, we observed limitations in the reactivity of alkyl and heteroaromatic amines. The processes enabled the synthesis of 20 novel C1-branched glycoamides and 7 new d-gluco esters., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Spleen tyrosine kinase (Syk) is a key signal transduction mediator of the B cell receptor (BCR) signaling pathway. Abnormal BCR signaling plays a key role in initiation and development of B-cell-derived hematological malignancies, therefore, Syk represents a potential target for inhibiting the BCR signaling resulting in a therapeutic effect in these cancers. Herein, we describe a novel series of SYK inhibitors with 4-(3'-pyrazolyl)-2-amino-pyrimidine scaffold. Extensive study of structure-activity relationships led to the identification of 1 (NMS-0963), a highly potent Syk inhibitor (IC 50  = 3 nM) endowed with high selectivity within a panel of tested kinases and high antiproliferative activity in SYK-dependent BaF3-TEL/SYK cells and in other BCR-dependent hematological tumor cell lines. Additionally, 1 effectively inhibited Syk phosphorylation and downstream signaling mediators of the BCR in treated cells. In in vivo pharmacokinetics studies, 1, displayed good pharmacokinetics properties, with linear exposure with dose and excellent oral bioavailability. These findings suggest that 1 is a promising new Syk inhibitor for treating BCR-dependent hematological cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Selenium-containing compounds have emerged as promising treatment for redox-based and inflammatory diseases. This study aimed to investigate the in vitro and in vivo anti-inflammatory activity of a novel diselenide named as dibenzyl[diselanediyIbis(propane-3-1diyl)] dicarbamate (DD). DD reacted with HOCl ( k  = 9.2 x 10 7 M -1 s -1 ), like glutathione ( k  = 1.2 x 10 8 M -1 s -1 ), yielding seleninic and selenonic acid derivatives, and it also decreased HOCl formation by activated human neutrophils (IC 50 =4.6 μM) and purified myeloperoxidase (MPO) (IC 50 =3.8 μM). However, tyrosine, MPO-I and MPO-II substrates, did not restore HOCl formation in presence of DD. DD inhibited the oxidative burst in d HL-60 cells with no toxicity up to 25 µM for 48h. Next, an intraperitoneal administration of 25, 50, and 75 mg/kg DD decreased total leukocyte, neutrophil chemotaxis, and inflammation markers (MPO activity, lipid peroxidation, albumin exudation, nitrite, TNF-α, IL-1β, CXCL1/KC, and CXCL2/MIP-2) on a murine model of carrageenan-induced peritonitis. Likewise, 50 mg/kg DD (i.p.) decreased carrageenan-induced paw edema over 5h. Histological and immunohistochemistry analyses of the paw tissue showed decreased neutrophil count, edema area, and MPO, carbonylated, and nitrated protein staining. Furthermore, DD treatment decreased the fMLP-induced chemotaxis of human neutrophils (IC 50 =3.7 μM) in vitro with no toxicity. Lastly, DD presented no toxicity in a single-dose model using mice (50 mg/kg, i.p.) over 15 days and in Artemia salina bioassay (50 to 2000 µM), corroborating findings from in silico toxicological study. Altogether, these results demonstrate that DD attenuates carrageenan-induced inflammation mainly by reducing neutrophil migration and the resulting damage from MPO-mediated oxidative burst.

Background: Usual interstitial pneumonia (UIP) is the radiologic and histologic hallmark of idiopathic pulmonary fibrosis (IPF) and the commonest histologic pattern of other progressive fibrosing interstitial lung diseases (e.g., fibrotic hypersensitivity pneumonia). Analogous to lung cancer, activation of epithelial-to-mesenchymal transition (EMT) is one of the main molecular pathways recently identified by transcriptomic studies in IPF. Fibroblastic foci (FF) are considered the active/trigger component of UIP pattern. The proto-oncogene C-MET is a key gene among molecules promoting EMT against which several inhibitors are currently available or promising in ongoing studies on lung cancer., Methods: Twenty surgical cases of diffuse fibrosing interstitial lung diseases (fILD) with UIP pattern and FF-rich (17 IPF and 3 patients with fibrotic hypersensitivity pneumonia, fHP) were retrospectively selected. FF were manually microdissected and analysed for c-MET gene alterations (FISH amplification and gene hot-spot mutations Sanger sequencing) and tested with a c-MET companion diagnostic antibody (clone SP44 metmab) by immunohistochemistry., Results: FF are characterized by upregulation of c-MET as shown by overexpression of the protein in 80% of cases, while no gene amplification by FISH or mutations were detected. C-MET upregulation of FF was observed either in IPF and fHP, with a tropism for the epithelial cell component only., Conclusion: Upregulation of c-MET in FF of ILD with UIP pattern further confirms the key role of the proto-oncogene c-MET in its pathogenesis, possibly representing an interesting and easily-detectable molecular target for selective therapy using specific inhibitors in future clinical trials, similar to lung cancer. It is reasonable to speculate that molecular alterations in FF can also be detected in FF by transbronchial cryobiopsy., (Copyright © 2023 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

In Winter 2020, Italy, and in particular the Lombardy region, was the first country in the Western hemisphere to be hit by the COVID-19 pandemic. Plasma from individuals recovered from COVID-19 (COVID-19 convalescent plasma, CCP) was the first therapeutic tool adopted to counteract the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In this retrospective cohort study, we report the experience of the city hospital of Mantua, Lombardy region, on the compassionate use of CCP in patients hospitalized for severe COVID-19. Between April 2020 and April 2021, 405 consecutive COVID-19 patients received 657 CCP units with a median anti-SARS-CoV-2 neutralizing antibody (nAb) titer of 160 (interquartile range (IQR), 80−320). Their median age was 68 years (IQR, 56−78 years), and 62% were males. At enrollment, 55% of patients had an increased body mass index (BMI), and 25.6% had at least three comorbidities. The 28-day crude mortality rate was 12.6% (51/405). Young age (<68 years), mild disease (admission to low-intensity departments) and early treatment (<7 days from symptoms onset) with high nAb titer (≥320) CCP were found as independently associated with a favorable response to CCP treatment. No safety concerns were recorded, with a rate of CCP-related adverse reactions (all of mild intensity) of 1.3%. In our real-life experience, the first in the western world, early administration of high-titer CCP was a safe and effective treatment for hospitalized COVID-19 patients.

Coronavirus disease (COVID-19) may predispose patients to pulmonary embolism (PE), despite standard thromboprophylaxis. Our retrospective study aimed to report the prevalence of PE in patients with COVID-19 and severe respiratory failure (SRF) treated with intermediate- to full-dose enoxaparin. We analyzed data from patients with COVID-19 pneumonia and SRF admitted to our Respiratory Intensive Care Unit (RICU) from February 27 to April 20, 2020. All patients received at least intermediate-dose enoxaparin (40 mg twice daily). Computed tomography pulmonary angiography (CTPA) was used to detect PE. Ninety-two patients with COVID-19 pneumonia and SRF were admitted to our RICU. Twenty-two patients underwent CTPA (24 %), 11 of whom had PEs (12%). We hypothesize that the enoxaparin treatment may be responsible for the lower prevalence of PE as compared to previous reports of similar patients, even if our report had several limitations, mainly the small sample size.

Background: The pandemic of new severe acute respiratory syndrome (SARS) due to coronavirus (CoV) 2 (SARS-CoV-2) has stressed the importance of effective diagnostic and prognostic biomarkers of clinical worsening and mortality. Epidemiological data showing a differential impact of SARS-CoV-2 infection on women and men have suggested a potential role for testosterone (T) in determining gender disparity in the SARS-CoV-2 clinical outcomes., Objectives: To estimate the association between T level and SARS-CoV-2 clinical outcomes (defined as conditions requiring transfer to higher or lower intensity of care or death) in a cohort of patients admitted in the respiratory intensive care unit (RICU)., Materials and Methods: A consecutive series of 31 male patients affected by SARS-CoV-2 pneumonia and recovered in the respiratory intensive care unit (RICU) of the "Carlo Poma" Hospital in Mantua were analyzed. Several biochemical risk factors (ie, blood count and leukocyte formula, C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), ferritin, D-dimer, fibrinogen, interleukin 6 (IL-6)) as well as total testosterone (TT), calculated free T (cFT), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were determined., Results: Lower TT and cFT were found in the transferred to ICU/deceased in RICU group vs groups of patients transferred to IM or maintained in the RICU in stable condition. Both TT and cFT showed a negative significant correlation with biochemical risk factors (ie, the neutrophil count, LDH, and PCT) but a positive association with the lymphocyte count. Likewise, TT was also negatively associated with CRP and ferritin levels. A steep increase in both ICU transfer and mortality risk was observed in men with TT < 5 nmol/L or cFT < 100 pmol/L., Discussion and Conclusion: Our study demonstrates for the first time that lower baseline levels of TT and cFT levels predict poor prognosis and mortality in SARS-CoV-2-infected men admitted to RICU., (© 2020 American Society of Andrology and European Academy of Andrology.)

Rationale: Methods for isomer discrimination by mass spectroscopy are of increasing interest. Here we describe the development of a three-dimensional ion trap for infrared multiple photon dissociation (IRMPD) spectroscopy that enables the acquisition of the infrared spectrum of selected ions in the gas phase. This system is suitable for the study of a myriad of chemical systems, including isomer mixtures., Methods: A modified three-dimensional ion trap was coupled to a CO 2 laser and an optical parametric oscillator/optical parametric amplifier (OPO/OPA) system operating in the range 2300 to 4000 cm -1 . Density functional theory vibrational frequency calculations were carried out to support spectral assignments., Results: Detailed descriptions of the interface between the laser and the mass spectrometer, the hardware to control the laser systems, the automated system for IRMPD spectrum acquisition and data management are presented. The optimization of the crystal position of the OPO/OPA system to maximize the spectroscopic response under low-power laser radiation is also discussed., Conclusions: OPO/OPA and CO 2 laser-assisted dissociation of gas-phase ions was successfully achieved. The system was validated by acquiring the IRMPD spectra of model species and comparing with literature data. Two isomeric alkaloids of high economic importance were characterized to demonstrate the potential of this technique, which is now available as an open IRMPD spectroscopy facility in Brazil., (© 2019 John Wiley & Sons, Ltd.)

Background and Aim of the Study: Maternal breastmilk represents the best nourishment for the newborn baby during its first six months, as it offers several benefits for the health and well-being of babies and mothers. In order to promote, protect and support effectively mother and child during breastfeeding, it is essential for midwives to be properly educated and to acquire highly professionalizing skills. This study aimed to evaluate the level of self-efficacy of the students attending the Degree Course of Midwifery, regarding the support of mother and child in breastfeeding., Method: A questionnaire of 37 items (Blackmanet al, 2015) validated in Italian by Mazzeo Melchionda (2019), was sent on-line to students of ten different Midwifery Degree Courses to assess their level of self-efficacy regarding the management of breastfeeding. Statistical analysis was carried out using statistic software R3.4.3 (The Foundation for Statistical Computing)., Results: 158 questionnaires were collected from ten Italian Midwifery Degree Courses. The areas in which students showed a high level of self-efficacy in managing breastfeeding include: the benefits of breastfeeding; the child's tendency to take the breast within an hour from childbirth and the relevance of skin to skin contact and rooming-in. Low levels of self-efficacy concerned the comfortably breastfeeding in public places and avoiding giving formula to the baby in its first six weeks of life., Conclusions: Generally the students attending Midwifery Degree Courses show a high level of self-efficacy in assisting mothers during breastfeeding and they prove to have a good knowledge of the benefits of breastfeeding to improve the health of mothers and their children. (www.actabiomedica.it).

Infrared photodissociation analyses are supported by theoretical calculations that allow a trustworthy interpretation of experimental spectra of gaseous ions. B3LYP calculations are the most prominent method used to model IR spectra, as detailed in our bibliographic survey. However, this and other commonly used methods are known to provide inaccurate energy values and geometries, especially when it comes to long-range interactions, such as intramolecular H-bonds, which show increased anharmonicity. Therefore, we evaluated some of the most commonly used density functional theory methods (B3LYP, CAM-B3LYP, and M06-2X) and basis sets (6-31+G(d,p), 6-311++G(d,p), 6-311++G(3df,2pd), aug-cc-pVDZ, and aug-cc-pVTZ), including anharmonicity and dispersion corrections. The results were compared to MP2 calculations and to experimental high-frequency (2000-4000 cm -1 ) IR multiphotonic dissociation (IRMPD) spectra of two protonated model molecules containing intramolecular hydrogen bonds: biotin and tryptophan. M06-2X/6-31+G(d,p) was shown to be the most cost-effective level of theory, whereas CAM-B3LYP was the most efficient method to describe the van der Waals interactions. The use of the dispersion correction D3, proposed by Grimme, improved the description of O-H vibrations involved in H-bonding but worsened the description of N-H stretches. Anharmonic calculations were shown to be extremely expensive when compared to other approaches. The efficiencies of well-established scaling factors (SFs) in opposition to sample-dependent SFs were also discussed and the use of fitted SFs were shown to be the most cost-effective approach to predict IRMPD spectra. M06-2X/6-31+G(d,p) and CAM-B3LYP/aug-cc-pVDZ were also tested against the fingerprint region. Our results suggest that these methods can also be used for analysis in this lower frequency range and should be regarded as the methods of choice for cost-effective IRMPD simulations rather than the ubiquitous B3LYP method, especially when further molecular properties are needed., Competing Interests: The authors declare no competing financial interest.

The aim of this study is to investigate thrombogenesis and the hypercoagulable changes in pregnant women affected by thrombophilia who received low-molecular-weight heparin (LWMH) prophylaxis. We included 21 pregnant women affected by thrombophilia treated with LWMH and 20 nontreated normal pregnant women as the control group. The sample group of thrombophilic pregnant women included different conditions (factor V Leiden mutation, protein C deficiency, protein S deficiency, antiphospholipid antibodies syndrome, and combined defects). Three blood samples were collected during pregnancy (i.e., at 16, 20, and 24 weeks) and tested for activated partial thromboplastin time and prothrombin fragment F1 + 2 (F1 + 2); anti-FXa activity was tested only in treated thrombophilic pregnant women. F1 + 2 levels progressively increased during pregnancy in both study groups. However, the F1 + 2 increase in women exposed to heparin prophylaxis was significantly lower than that in normal pregnant women in all 3 measurements carried out during gestation (p < 0.05); a statistically significant inverse correlation between F1 + 2 levels and anti-Xa activity (R = -0.8575, p < 0.05) was observed in treated women during pregnancy. Our findings suggest that F1 + 2 in addition to anti-Xa measurement could be used to adjust LWMH prophylaxis, at least in high-risk pregnant women., (© 2017 S. Karger AG, Basel.)

Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis. These compounds induced an increased affinity for nucleotides. Interference with nucleotide turnover in individual subunits and distortion of interprotomer communication cooperated to impair VCP enzymatic activity. Chemical expansion of this allosteric class identified NMS-873, the most potent and specific VCP inhibitor described to date, which activated the unfolded protein response, interfered with autophagy and induced cancer cell death. The consistent pattern of cancer cell killing by covalent and allosteric inhibitors provided critical validation of VCP as a cancer target.

A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure-activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Gastro-Intestinal Stromal Tumors (GISTs) represent an evolving field in oncological surgery and must be approached with specific prognostic and therapeutic criteria. In the GIST's suspicion the surgeon has to consider all the therapeutic possibilities, also for the impossibility to predict the biological behaviour and the aggressiveness of the tumor. The presence of a GIST has to be suspected in patients observed for gastrointestinal bleeding, when another pathology isn't demostrable. Surgical strategy must consider a limited resection as the best treatment, differently from what we do for adenocarcinoma. The extension of the resection can changes, regarding tumor volume and position, from extremely invasive surgery to laparoscopic operations with a partial removal of the gastric wall. Lymphadenectomy is not indicated because these tumors rarely spread to the nodes. We present the clinical case of two patients observed for gastrointestinal bleeding and with preoperative diagnostic suspicion of GIST, submitted to surgical resection. In the first case we performed a superior polar gastrectomy with esofago-gastric anastomosis for the mass proximity to the cardias. In the second patient the intervention has been a limited resection of the fundus of stomach including the tumor.

The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.

Gastrointestinal stromal tumors are mesenchymal neoplasms of the gastrointestinal tract that represent less than 1% of all GI tumors. Here the case of such a tumour that, in addition to the classical features, also displayed chondroid differentiation is reported. Chromosomal abnormalities were also investigated.

Objective: To compare the use of a balloon catheter device with the use of a cervical vacuum cup device in performing hysterosalpingography (HSG)., Design: Prospective, randomized, single-blinded study., Setting: Tertiary infertility center., Patient(s): Two hundred twenty-nine infertile women undergoing HSG., Intervention(s): Subjects were randomized to undergo HSG using a cervical vacuum cup (n = 115) or a balloon catheter (n = 114). Randomization was performed according to Consolidated Standard of Reporting Trials (CONSORT) guidelines., Main Outcome Measure(s): The degree of pain experienced during and after the HSG, evaluated using a 100-mm visual analogue scale. The length of the procedure, the fluoroscopic time, the volume of contrast used, the difficulty of performing HSG, and the percentage of complications were also evaluated., Result(s): Women in the cervical-cup group experienced more pain than those in the balloon catheter group during the contrast injection (median visual analogue scale pain scores, 13.0 vs. 6.5). The placement of the balloon catheter in comparison with the cervical cup was slightly easier to perform, although it required a somewhat longer time. The HSG using the cervical cup required less fluoroscopic time (median, 0.6 vs. 0.8 min)., Conclusion(s): The balloon catheter appears to be better tolerated than the cervical cup, but the difference is minimal. The use of the cervical cup allows shortening of the patient radiation exposure.

A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several diversity sites, was linked to various resins through the primary (C-6) hydroxyl and decorated on the solid phase: the hydroxyl group at C-4 was functionalized as ester, ether, and carbamate, the amino group in the second cycle (C-3' position) was functionalized as amide, sulfonamide, and ureido- and thioureido-derivatives. The compounds synthesized on the solid phase were tested for their antiproliferative activity on tumor cell lines.

We report a case of neuroma of the common hepatic duct arising five years after cholecystectomy (laparoscopic then converted in laparotomy). A 73-years-old patient was admitted for obstructive jaundice. Ultrasonography, TC and cholangiography showed a nodular lesion of the common hepatic of 1 cm in diameter, causing a regular and important stenosis of the main bile duct. Histologic examination demonstrated neuroma. By the analysis of this and 42 other previously published cases, the following features of bile duct neuroma were outlined: 1) variable interval between cholecystectomy and the onset of jaundice (2 months to 40 years); 2) the same incidence after laparoscopic or laparotomic cholecystectomy; 3) the generally complicated postoperative course after first surgical approach; 4) the various localizations on the biliary tree (cystic, main bile duct, intrahepatic ducts); 5) the circumstances of onset are almost the same (obstructive jaundice); 6) the histologic examination is mandatory for a correct diagnosis; and 7) the best treatment is resection of the bile duct tract involved in neuroma and reconstruction of biliary tree with hepaticojejunostomy.

The availability of small organic molecules covering as much chemical space as possible is seen as the only means that guarantees potential modulation of the many biological targets that are ultimately being unveiled by genomics. Therefore diversity oriented organic synthesis is rapidly becoming one of the paradigms in the process of modern drug discovery. This has spurred research in those fields of chemical investigation that lead to the rapid assembly of not only molecular diversity, but also molecular complexity. As a consequence multi-component as well as domino or related reactions are witnessing a new spring. Coupling these one-pot processes with solid-phase synthesis offers new perspectives for the preparation of both primary and thematic libraries. The progresses recently made in this field that perfectly suits the needs of modern drug discovery are the subject of the present review.

The incidence of extrahepatic gastrointestinal metastases from breast cancer is reported in the literature only as necroscopy studies (6-18 percent); they usually originate from lobular or a mixed ductal-lobular subtype. Nonspecific presenting symptoms, death of the patients caused by other more frequent metastases, and variable radiographic features mimicking primary neoplasms cause a clinical underestimation of this pathology. We report here a case of rectal metastasis from a lobular carcinoma eight years after mastectomy.

Metastatic disease involving the gastrointestinal tract is a rare pathology and melanoma is the extra-intestinal neoplasm more frequently concerned. Two cases of gastric metastases, revealed by symptoms of upper gastrointestinal bleeding, are reported. In the first case the disease-free interval, after excision of the primary lesion located in the right lower limb, was 13 years; in the second case the primary lesion remained unknown, although it probably originated from a giant congenital nevus of the left foot. Both patients had been affected before by inguinal nodes metastases, treated by radical groin lymphadenectomy; the concomitant multiple metastases to other sites (adrenal glands, retro-peritoneum, liver, lung, small bowel, brain, ovaries) limited surgery to a likely prospect of palliation, conditioning an unfavourable prognosis. Resection of gastrointestinal metastases is justified for the relief of intestinal hemorrhage (as in these reported cases), perforation and obstruction, even if treatment of single non-complicated lesions can have a curative intent. The conclusion is drawn that more aggressive diagnostic and staging procedures are indicated for the early detection of gastrointestinal metastases whenever non-specific abdominal symptoms and a history of melanoma are present.

A clinical report concerning a severe idiopathic thrombocytopenia during pregnancy (minimal platelet count 3000/mm3 is described). Corticosteroids and immunoglobulins were administered in preparation to elective cesarean delivery. Since the platelet count not improve significantly, 3 units of platelets from a single donor were adjunctively given using diapheresis. An elective cesarean delivery was performed at 34 weeks, without further complications. The newborn weighed 2550 g and the postnatal course was uneventful.

The anamnestic, clinical, laboratory, radiological and intraoperative data on 34 consecutive patients affected by acute intestinal ischemia or infarction, caused by superior mesenteric obstructive and nonocclusive pathology were collected and assessed. The aim of this study is the identification of the factors influencing the prognosis which in this disease is still really displeasing, with a mortality of over 90% in many surveys, and 73.5% in this report. The mean age of the 34 patients was 73. Cardiac ischemic disease and or arrhythmias were present in 83.8% of the patients. The most significant prognostic factors were those related to the evolutive stages of the intestinal ischemia. Among the anamnestic ones, the interval between the onset of the symptoms and diagnosis (mortality of 50% if less than or equal to 24 hrs., 86.4% if greater than 24 hrs.). Among the clinical factors, the presence of peritoneal signs was followed by a mortality of 82.3%, in contrast with the 33.3% when the same signs were absent. Also significant was the presence of shock (100% mortality), in contrast with 50% in patients presenting systemic systolic pressure greater than 100 mmHg. Extensive intestinal infarction caused a 100% mortality rate, while early revascularization allowed the survival of 81.8% of the patients treated in the absence of infarction or when irreversible ischemic damage was limited to less than 1 meter of bowel.

One hundred seventy patients with M0 bronchogenic carcinoma were preoperatively evaluated by CT staging whose results were correlated with surgical findings. A number of over and understaging were observed in assessing mediastinal nodes involvement, chest wall invasion, mediastinal pleura and vessels invasion as well as pulmonary vessels involvement. In conclusion, the Authors believe that no patient surgical indication should be excluded on the basis of CT evidence of intrathoracic invasion, in the light of the demonstrated potential for false-positive diagnoses.

Twenty-eight patients with advanced breast cancer, all previously treated with hormonotherapy and/or chemotherapy, entered this study. Treatment was comprised of 5-day courses of folinic acid (200 mg/m2/day by i.v. bolus injection) and 5-fluorouracil, given immediately afterwards at a dose of 340-370-400 mg/m2/day according to toxicity. Cycles were repeated every 28 days. The remission rate was 60.7% (17/28): 10.7% CR (complete) (3/28), 50% PR (partial) (14/28), while 35% (1/28) had no change. Fourteen out of 23 patients previously treated with 5-FU also responded. The median duration of remission was about 6 months. Hematological toxicity was mild, while gastroenteric and ocular side-effects were important, even if not life-threatening. These data suggest that 5-FU combined with high-doses of folinic acid is effective in advanced breast cancer.

Proglumetacin at low-dose (300 mg/day) and naproxen (500 mg/day) were used in a crossover study in 20 patients with primary polyarthrosis. Each drug was administered during 1 week without between drugs. Both drugs resulted effective in the management of the most disturbing symptoms, without significant differences. Tolerance was also superimposable, as the few reported complaints were recorded under both treatments and appeared rather related to the patient than to the drug. Proglumetacin therefore, even when given at low dose, resulted at least as effective as an established treatment for polyarthrosis, while confirming its very good tolerance, so as to appear well suited for the general management of patients with such degenerative-reactive disorders.

Thirty-three patients with advanced breast cancer were treated with combination chemotherapy and hormonal synchronization in an attempt to increase the overall response rate generally obtained with traditional modalities of treatment. Among the 31 evaluable patients 1 complete (3%), 7 partial (22%), 13 stable disease (42%) and 10 progression of disease (53%) were obtained. Side effects were quite manageable although there were two episodes of life-threatening hematological toxicity. Taking into account the poor prognostic characteristics of our patients (high percentage of dominant visceral disease, 21/31 previously treated patients), our preliminary results with this regimen are interesting and the treatment deserves further evaluation.

The results are reported of an open multicentre trial in 228 rheumatic patients with flare-ups. Fourteen centres adopting the same investigational protocol collaborated in the study. Indoprofen was administered for 1 week at a daily dosage of 1000 mg according to a treatment schedule used with success in acute gouty arthritis: a 400 mg i.v. bolus was followed by 200 mg (1 tablet) t.i.d. Subjective (pain) and objective variables were used for reliable assessment of activity. Marked reduction of pain intensity was already noticeable on day 1 of treatment and was followed by progressive improvement in subjective and objective variables for all the diagnoses considered. According to the patients' own overall assessments, results were good or very good in more than 50% of cases. The best outcomes were obtained in low back pain, acute gout and psoriatic arthritis. At the end of treatment only 7.4% of patients experienced no change or deterioration of symptoms. Adverse reactions, consisting mostly of mild and reversible gastrointestinal disturbances, were reported by 9.2% of patients, but only in 1.8% was treatment discontinued. Indoprofen administered according to the above schedule is an appropriate treatment for acute episodes of rheumatic diseases.